Cerebrovascular diseases have become one of the major leading causes of death in China, and better therapeutic agents for treatment of acute ischemic cerebral stroke are needed all over the world. Thrombolytic agent, t-PA, which was approved by U.S. Food and Drug Administration (FDA) in 1996, has contentious therapeutic effect on these diseases due to its side effect related to high risk of encephalic bleeding. The results of studies on various cerebral protective agent has shown that the clinical therapeutic effects of many medicaments are either insufficient, or have relatively severe side effects. Several medicaments are still in the phase of clinical trial.
In recent more than 10 years, the present inventors have found that racemic butylphthalide (or butylphthalide, NBP) is a drug that has significant therapeutic effect on acute ischemic cerebral stroke. The pharmacodynamical characteristics thereof include: 1. improving energy metabolism of the ischemic brain; 2. significantly reducing the area of cerebral infarct induced by focal cerebral ischemia in rat, and alleviating deficit of neural function; 3. alleviating the cerebral edema induced by focal cerebral ischemia; 4. significantly improving the focal cerebral blood flow in ischemic area and micro-circulation in cerebral pia mater of rats; and 5. significantly alleviating the memory disorder induced by focal cerebral ischemia.
Moreover, it has less toxic side effect. The present applicant has obtained two use patents on the related field in China, which is China Patent No. ZL93117148 titled “Use of butylphthalide in the manufacture of medicaments for prevention and treatment of diseases induced by cerebral ischemia” issued in 1999, and Chinese Patent No. ZL98125618.X titled “Use of butylphthalide in the manufacture of anti-thrombosis medicaments” issued in 2002 under the International Patent Classification No. A61K31/34, respectively.
After the pre-clinical studies, clinical trials of phase II and phase III were conducted on 542 cases, in which there are 192 cases using multi centered, random, double blinded placebo control. It was found that the total effective rate in the administration group is 70.7%, and the rate in placebo group is 41.0%. Thus good therapeutic effect was obtained. The New Drug Certificate and Production License for the class I new drug have been approved on NBP for the treatment of acute ischemic cerebral stroke by the State Drug Administration of China in 2002 (National Drug License Nos. H20020374; H20020375; 2002H0551, and 2002H0552).
Chemical resolution was conducted on racemic butylphthalide (simplified as dl-NBP hereinafter), and levo-butylphthalide (simplified as l-NBP hereinafter) and dextro-butylphthalide (simplified as d-NBP hereinafter) are obtained separately. The present applicant has filed a China Patent Application No. 99109673.8 with a Publication No. CN1283621A, the title of which is “A method for preparing the optical active 3-n-butylphthalide”. Furthermore, the function of L-butylphthalide was not mentioned in the previous China Patent No. ZL93117148.